Melanocortins are peptides derived from pro-opiomelanocortins (POMC) that bind to and activate G-protein coupled receptors (GPCR's) of the melanocortin receptor family. Melanocortins regulate a diverse number of physiological processes including sexual function and sexual behaviour, food intake and metabolism. There are five melanocortin receptors that have been cloned, MCR1, MCR2, MCR3, MCR4, MCR5, and are expressed in various tissues. MCR1 is specifically expressed in melanocytes and melanoma cells, MCR2 is the ACTH receptor and is expressed in adrenal tissue, MCR3 is predominantly expressed in the brain and limbic system, MCR4 is widely expressed in the brain and spinal cord, and MCR5 is expressed in the brain and many peripheral tissues including skin, adipose tissue, skeletal muscle, and lymphoid tissue. MCR3 may be involved in the control of sexual function, food intake and thermogenesis.
MCR4 is a G-protein-coupled seven-transmembrane receptor primarily expressed in the hypothalamus, hippocampus, and thalamus (Gantz et al. 1993 J Biol Chem 268:15174-15179). The receptor is implicated in the central regulation of body weight: MCR4 is activated by α-melanocyte-stimulating hormone (MSH), which is derived from pro-opiomelanocortin and is inactivated by agouti gene-related protein (AGRP). α-MSH induces weight loss, whereas the ectopic expression of agouti protein results in obesity in the agouti mice (Fan et al. 1993 Nature 385:165-168; Lu et al. 1994 Nature 371:799-802). Additional evidence for the role of MCR4 in weight regulation stems from both a knockout model in mice (Huszar et al. 1997 Cell 88:131-141) and haploinsufficiency mutations in humans (Vaisse et al. 1998 Nat Genet 20:113-114; Yeo et al. 1998 Nat Genet 20:111-112; Hinney et al. 1999 J Clin Endocrinol Metab 84:1483-1486). In MCR4-knockout mice, an increased body weight was discernible by age 5 wk. By age 15 wk, homozygous mutant females were, on average, twice as heavy as their wild-type littermates, whereas homozygous mutant males were ˜50% heavier than wild-type controls. Mice heterozygous for the MCR4-knockout showed a weight gain intermediate to that seen in wild-type and homozygous mutant littermates, thus demonstrating a gene dosage effect of MCR4 ablation on body-weight regulation. The food intake of homozygous mutants was increased by ˜50% in comparison to that in wild-type sibs (Huszar et al. 1997 Cell 88:131-141). [From Am. J. Hum. Genet., 65:1501-1507, 1999]. MCR4 activation has been shown to induce penile erection in rodents and MCR4 inactivation has been shown to cause obesity (reviewed in Hadley, 1999, Ann N Y Acad. Sci., 885:1-21, Wikberg et al 2000, Pharmacol Res., 42(5), 393-420).
Chaki and Nakazato, in Drugs Of The Future, 2004, 29(10): 1065-1074, refer to potential therapeutic applications for ligands acting at the MC4 receptor. Diazepine derivatives are reported in WO 95/00497, WO 97/17973, WO 98/07692, WO 98/20001, WO 2006/040192 and EP 1867639. Inhibitors of FXa are reported in WO 98/54164. Compounds useful for treating bone deficit conditions are reported in WO 99/42107. Antagonists of H3 receptors are reported in WO 02/072570. Modulators of PPAR are reported in US 2005/0234046.
The compounds of the present invention are useful in treating diseases, disorders or conditions responsive to activation of the MC4 receptor, including:                male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and/or sexual pain disorder in females, male erectile dysfunction;        obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving); and        diabetes mellitus (by enhancing glucose tolerance and/or decreasing insulin resistance).        
The compounds of the invention are potentially useful in treating further diseases, disorders or conditions including, but not limited to, hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, fever, inflammation, immune modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease, treatment of Lower Urinary Tract Dysfunction (including Urinary Incontinence—overactive bladder, increased daytime frequency, nocturia, urgency, urinary incontinence (any condition in which there is an involuntary leakage of urine), including stress urinary incontinence, urge urinary incontinence and mixed urinary incontinence, overactive bladder with associated urinary incontinence, enuresis, nocturnal enuresis, continuous urinary incontinence, situational urinary incontinence such as incontinence during sexual intercourse, and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)), and any other indications mentioned in the above-referenced patent applications.
The compounds of the present invention are particularly suitable for treating female sexual dysfunction, male erectile dysfunction, obesity, diabetes, and conditions of Lower Urinary Tract Dysfunction.
The terms “treating”, “treat”, or “treatment” as used herein are intended to embrace both prevention and control i.e., prophylactic, and palliative treatment of the indicated conditions.
Desirable properties for MCR4 agonist compounds of the present invention include: desirable MCR4 agonist potencies as detailed hereinafter; selectivity for MCR4 agonism versus MCR1, and/or MCR5, and/or MCR3 as detailed hereinafter; both desirable MC4R agonist potency and selectivity for MCR4 versus, MCR1, and/or MCR5, and/or MCR3; good biopharmaceutical properties such as physical stability; solubility; oral bioavailability; appropriate metabolic stability.